CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16

Li, Tao; Xie, Qi; Ding, Yue-He; Li, Shang-Tong; Shan, Peng; Zhang, Yanping; Tan, Dan; Yuan, Zengqiang; Dong, Meng‐Qiu

doi:10.7554/elife.00518

Cited by 49 publications

(45 citation statements)

References 50 publications

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“…Highlighting the role of inter-tissue communication in AMPK longevity, tissue-specific activation of AMPK in the fly promotes systemic tissue homeostasis via the autophagic effector, Atg1, which subsequently and cell-nonautonomously promotes activation of autophagy in other tissues (Ulgherait et al, 2014). DAF-16/FOXO is a known regulator of autophagy and is directly regulated by both AMPK and calcineurin and required for their effects on longevity (Greer et al, 2007; Tao et al, 2013). We saw enrichment of the DAE element in genes downregulated when both AMPK and CRTC-1 were active, suggesting CRTC-1 might remotely regulate DAF-16/FOXO activity and/or activate its transacting antagonist PQM-1 (Tepper et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Burkewitz

Morantte

Weir

et al. 2015

Cell

182

232

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SUMMARY Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

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Section: Discussionmentioning

confidence: 99%

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Burkewitz

Morantte

Weir

et al. 2015

Cell

182

232

View full text Add to dashboard Cite

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“…For instance, Pak1/Camkk-beta was first identified in yeast as Snf-1/AMPK-activating kinase and was proven later to act upstream of AMPK in mammalian systems [85], [86], [87]. Very recently, CAMKII overexpression was shown to increase lifespan in C. elegans , although the link to AAK-2 was not investigated [88].Together, our data demonstrate that FLCN-1-dependent regulation of AAK-2 mediates an important novel pathway for stress resistance. Interestingly, this pathway is distinct from previously described AAK-2-mediated oxidative stress resistance mechanisms that involve ROS detoxification [51], [52], [89].…”

Section: Discussionmentioning

confidence: 99%

Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival

et al. 2014

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Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.

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“…Lifespan assays were performed as described previously (Tao et al 2013). All lifespan assays were conducted at 20°C starting from the first day of adulthood.…”

Section: Lifespan Assaymentioning

confidence: 99%

Profiling the RNA editomes of wild-type C. elegans and ADAR mutants

et al. 2014

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RNA editing increases transcriptome diversity through post-transcriptional modifications of RNA. Adenosine deaminases that act on RNA (ADARs) catalyze the adenosine-to-inosine (A-to-I) conversion, the most common type of RNA editing in higher eukaryotes. Caenorhabditis elegans has two ADARs, ADR-1 and ADR-2, but their functions remain unclear. Here, we profiled the RNA editomes of C. elegans at different developmental stages of wild-type and ADAR mutants. We developed a new computational pipeline with a ''bisulfite-seq-mapping-like'' step and achieved a threefold increase in identification sensitivity. A total of 99.5% of the 47,660 A-to-I editing sites were found in clusters. Of the 3080 editing clusters, 65.7% overlapped with DNA transposons in noncoding regions and 73.7% could form hairpin structures. The numbers of editing sites and clusters were highest at the L1 and embryonic stages. The editing frequency of a cluster positively correlated with the number of editing sites within it. Intriguingly, for 80% of the clusters with 10 or more editing sites, almost all expressed transcripts were edited. Deletion of adr-1 reduced the editing frequency but not the number of editing clusters, whereas deletion of adr-2 nearly abolished RNA editing, indicating a modulating role of ADR-1 and an essential role of ADR-2 in A-to-I editing. Quantitative proteomics analysis showed that adr-2 mutant worms altered the abundance of proteins involved in aging and lifespan regulation. Consistent with this finding, we observed that worms lacking RNA editing were short-lived. Taken together, our results reveal a sophisticated landscape of RNA editing and distinct modes of action of different ADARs.

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CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16

Cited by 49 publications

References 50 publications

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival

Profiling the RNA editomes of wild-type C. elegans and ADAR mutants

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